5 Methylxanthines, B-phenethylamines Stimulants, Anorexients, ADHD

types of neurotransmitter receptors

ligand-gated ion channels, GPCRs

what are the monoamine neurotransmitters? are they excitatory, inhibitory or both?

- Ach, NE, E, dopamine, seratonin, histamine

- excitatory & inhibitory

is GABA excitatory, inhibitory or both?

inhibitory

is glutamate excitatory, inhibitory or both?

excitatory

CNS stimulants effects (intended effects and AE)

- increased alertness, decreased drowsiness & fatigue

- too much -> nervousness, anxiety, fatigue

CNS stimulants therapeutic uses

central sympathomimetic agents, antidepressants

methylxanthines examples

caffeine, theophylline, theobromine, aminophylline, pamabrom, dyphylline

methylxanthine MOA (3)

1. adenosine-1 (A1) antagonist, which increases cAMP (most important)

2. inhibits PDE, which increases cAMP

3. alters intracellular Ca2+ distribution

is caffeine acidic or basic? how does this affect solubility?

weakly basic, not very soluble at room temp

how to increase the solubility of methylxanthines

include acid to create a salt

caffeine indication

infant apnea, migraines (exedrin)

caffeine metabolism

oxidative demethylation

is caffeine lipophilic or hydrophilic? how does this effect CNS stimulation?

high lipophilicity due to methyl groups -> high absorption in BBB -> stimulates CNS

theophylline indications

bronchial asthma

theophylline administration

oral or IV

is theophylline acidic or basic? how does this affect solubility?

more acidic than caffeine -> more soluble than caffeine (but still limited water solubility at room temp, more soluble at warm temps)

theophylline metabolism

oxidative demethylation

what are salt derivatives of theophylline

aminophylline (2:1), oxtriphylline (1:1). pamabrom (1:1),

oxtriphylline indication

bronchial asthma (po or IV)

pamabrom indications

often used in combo with acetaminophen for back pain and menstural relief

dyphylline solubility compared to theophylline

better solubility -> doesn't need to be made into a salt

dyphylline indication

asthma, COPD

is theophylline a metabolite of dyphylline

no, dyphylline isn't dealkylated (not heavily metabolized)

is dyphylline stronger or weaker than theophylline? what is the benefit?

dyphylline is weaker -> less CNS stimulation, less likely to have excessive stimulation

doxapram administration

IV only

doxapram indication

respiratory stimulation after anesthesia or drug overdose

doxapram metabolism (what phase & reactions)

oxidative phase 1 reactions (oxidation, hydroxylation, dealkylation)

modafinil indication

narcolepsy, OSA

is modafinil racemic? if so, is one enantiomer more potent than the other?

yes, R isomer is more potent than S

what is armodafinil?

R enantiomer of modafinil

modafinil metabolism

hydrolysis, oxidation of sulfide

pitolisant HCL MOA

H3 inverse agonist and antagonist -> increases histamine release

pitolisant HCL administration, metabolism

- oral

- metabolized by CYP2D6

pitolisant HCL indications

narcolepsy, cateplaxy

solriamfetol structure

phenethyl amine

solriamfetol stereochemistry

R isomer only

solriamfetol indications

narcolepsy, OSA (obstructive sleep apnea)

solriamfetol longevity and half life

lasts for 9 hours, half life is 7.1 hours

is sodium oxybate a CNS depressant or stimulant

CNS depressant (strong sedative)

sodium oxybate MOA

GABA B and GHB agonist

sodium oxybate indications

narcolepsy (only inhibitory drug used), cateplaxy

sodium oxybate is the synthetic form of ...

GHB

when is sodium oxybate administered

night

how to improve the stability of B-phenylethylamines so that they can cause CNS stimulation

1. adding methyl group to alpha carbon -> resistant to MAO metabolism -< cross BBB

2. adding OMe to aromatic ring -> cross BBB

3. size of N group -> the bulkier the N, the less likely it will cross the BBB (no more than 1 methyl on the amine)

B-phenylethylamines MOA (4)

1. indirect CNS stimulation via adrenergic sympathetic NS (mimic NE, dopamine, serotonin)

2. promotes release of neurotransmitters & prevent reuptake of neurotransmitters

3. weak MAO inhibitors

what CNS structures do B-phenylethylamines stimulate

cortex, brain stem, medulla

B-phenylethylamines AE

hypertension (due to sympathetic stimulation)

B-phenylethylamines metabolism (location and reactions)

- in liver

- oxidative phase 1 reactions (aromatic hydroxylation, hydroxylation at benzylic position (a from benzyl), N-dealkylation, deamination)

how does urine pH affect half-life of unchanged B-phenylethylamines

B-phenylethylamines are basic -> increased urinary pH -> longer half life

since B-phenylethylamines have abuse potential, how can an overdose be treated?

administer ammonia chloride (NH4Cl) -> in the liver, metabolizes to urea + H30, which acidifies urine pH -> decreases half-life

what enantiomer of B-phenylethylamines is typically more potent and used

S enantiomer

what B-phenylethylamines are used as CNS stimulants

amphetamine, dextroamphetamine, methamphetamine

what is dextroamphetamine

the S-enantiomer of amphetamine

amphetamine, dextroamphetamine indication

ADHD

what is the major metabolite of amphetamine? is it active?

inactive phenylacetone (from MAO)

methamphetamine indications

- ADHD > 6 yo

- short term weight loss when other therapies haven't worked

is methamphetamine or amphetamine more active

methamphetamine

what enantiomer of methamphetamine is used?

S enantiomer

B-phenethylamine anorexiants examples

phentermine, benzphetamine, diethylproprion, phendimetrazine

B-phenethylamine anorexiants MOA

1. modulate NE, 5-HT, and dopaminergic pathways -> promotes release & prevent reuptake of neurotransmitters

2. inhibition of nutrient absorption from intestines, inhibition of lipid biosynthesis, enhancement of lipolysis, and delay of gastric emptying

how do N-substituents affect the abuse potential of B-phenethylamine anorexiants

the bulkier the N groups, the less abuse potential

phenteramine indication

appetite suppressant

do B-phenethylamine anorexiants or CNS stimulants have more abuse potential

B-phenethylamine CNS stimulants

why does phenteramine have a reduced abuse potential (schedule 4)

ion exchange resin -> slow release

how is phenteramine eliminated? can it be deaminated by MAO?

eliminated unchanged (MAO can't deaminate it because there's no H group on adjacent C?)

benzphetamine HCL indication

appetite suppressant

benzphetamine HCL metabolism

N-dealkylation, N-demethylation, aromatic hydroxylation

does phenteramine or benzphetamine HCL have more abuse potential? why?

benzphetamine HCL has higher abuse potential because it can be dealkylated to methamphetamine

diethylpropion HCL indication

weight loss

how do diethylpropion's side effects compare with phenteramine and benzphetamine

diethylpropion has less side effects

diethylpropion metabolism

N-dealkylation

is diethylpropion racemic?

yes

which CNS stimulant anorexiant is a prodrug? how is it activated?

phendimetrazine, activated by N-methylation

phendimetrazine stereochemistry

S,S

phendimetrazine indication

short term therapy of obesity

what is the non-CNS-stimulant weight loss drug

orlistat

orlistat MOA

irreversible inhibitor of pancreatic lipase -> prevents absorption of fatty acids and MAG -> increases excretion of fat

what part of orlistat interacts with pancreatic lipase

lactone

is orlistat avaliable OTC

yes

MOA of ADHD drugs

CNS stimulants inhibit dopamine transport away from synapse -> increased available dopamine

ADHD drugs

methylphenidate (dexmethylphenidate), serdexmethylphenidate, lisdexamfetamine, atomoxentine, viloxazine

which enantiomer of methylphenidate is more potent? what is it called?

- R,R (threo) isomer is more potent than S,S (erythro) isomer

- R,R is called dexmethylphenidate (Focalin)

methylphenidate (Ritalin) and dexmethylphenidate (Focalin) indications

narcolepsy, ADHD

methylphenidate major metabolites and whether they're active or inactive

- inactive: ritalinic acid, lactam

- active: p-hydroxy

Azstarys components

serdexmethylphenidate (schedule 4) + dexmethylphenidate (schedule 2)

what component of Azstarys is a prodrug? how is it activated

serdexmethylphenidate -> hydrolysis releases dexmethylphenidate at a slow rate

lisdexamfetamine indication

ADHD in children, binge eating disorder in adults

lisdexamfetamine stereochemistry and structure

dextral - steroid center in S configuration

is lisdexamfetamine a prodrug? how and where is it activated? what is it activated to?

yes, activated by hydrolysis in RBC -> releases dexmethylphenidate

what ADHD drugs are selective NE reuptake inhibitors (sNRIs) (not CNS stimulants)

atomoxetine, viloxazine

are sNRIs controlled substances?

no

atomoxetine indication

ADHD

atomoxetine metabolism

oxidative phase 1 reactions, mainly hydroxylation & glucoronidation on phenyl ring

is viloxanzine indicated for depression

not anymore, it used to be but was withdrawn

viloxanzine indication

ADHD, narcolepsy, cachexia

viloxanzine metabolism

hydroxylation of aromatic ring

viloxanzine selectivity

- very selective for NE (high Kd)

- not as selective for seratonin and dopamine (low Kd)

schedule 2 controlled substances CNS stimulants

ADHD: amphetamine, dexamphetamine, methamphetamine, methylphenidate, Azstaryz, lisdexamfetamine

schedule 3 controlled substances CNS stimulants

- CNS depressant: sodium oxybate

- anorexient: benzphetamine, phendimetrazine